The present invention is a process for the preparation of a compound of the formula 
wherein
R2a, R2b are, independently selected from the group consisting of hydrogen, halogen, lower alkoxy, cyano, xe2x80x94COOH, lower alkoxy carbonyl, lower alkyl and lower alkyl substituted by halogen;
R3a, R3b are, independently selected from the group consisting of hydrogen, lower alkyl and lower cycloalkyl, or alternatively, R3a and R3b taken together, are xe2x80x94(CH2)nxe2x80x94 wherein n=2, 3 or 5.
The compounds of formula I are valuable intermediate products for the preparation of therapeutically active compounds of formula 
wherein
R is hydrogen; lower alkyl; lower alkoxy; halogen; or trifluoromethyl;
(R1)m are, independently from each other, hydrogen or halogen; or
R and R1 may be together xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94;
R2a, R2b, R3a, R3b have the meanings mentioned above;
R4 is hydrogen; halogen; lower alkyl; lower alkoxy; xe2x80x94N(R5)2; xe2x80x94N(R5)S(O)2xe2x80x94 lower alkyl; xe2x80x94N(R5)C(O)R5 or a cyclic tertiary amine of the group 
R5 is, independently from each other, hydrogen; C3-6-cycloalkyl; benzyl; or lower alkyl;
R6 is hydrogen; hydroxy; lower alkyl; xe2x80x94N(R5)COxe2x80x94 lower alkyl; hydroxy-lower alkyl; cyano; xe2x80x94CHO; or a 5- or 6 membered heterocyclic group, optionally bonded via an alkylene group;
Y is a single bond; xe2x80x94(CH2)nxe2x80x94; xe2x80x94Oxe2x80x94; xe2x80x94Sxe2x80x94; xe2x80x94SO2xe2x80x94; xe2x80x94C(O)xe2x80x94; or xe2x80x94N(R5)xe2x80x94;
X is xe2x95x90Nxe2x80x94; xe2x80x94CHxe2x95x90; or xe2x80x94C(Cl)xe2x95x90;
W is xe2x80x94CHxe2x95x90; or xe2x95x90Nxe2x80x94;
m is 0,1,2,3 or 4.
Examples of compounds of formula II can be found among the 4-phenyl-pyridine derivatives such as 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide and among the 4-phenyl pyrimidin derivatives such as 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-morpholin-4-yl-4-o-tolyloxy-pyrimidin-5-yl)-isobutyramide. It has been surprisingly found that the compounds of formula II are antagonists of the neurokinin-1 (NK-1, substance P) receptor. Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The receptor for substance P is a member of the superfamily of G protein-coupled receptors.
Compounds of formula II are described e.g. in EP-A-1035115 and WO 00/50398.
The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.
As used herein, the term xe2x80x9clower alkylxe2x80x9d denotes a straight- or branched-chain alkyl group containing from 1-7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like. Preferred lower alkyl groups are groups with 1 to 4 carbon atoms. A preferred xe2x80x9clower alkyl substituted by halogenxe2x80x9d is trifluoromethyl.
The term xe2x80x9clower alkoxyxe2x80x9d denotes a group wherein the alkyl residues are as defined above, and which is attached via an oxygen atom.
The term xe2x80x9chalogenxe2x80x9d denotes chlorine, iodine, fluorine and bromine.
The term xe2x80x9ccycloalkylxe2x80x9d denotes a saturated carbocyclic group, containing 3-7 carbon atoms.
The term xe2x80x9ccyclic tertiary aminexe2x80x9d denotes, for example, pyrrol-1-yl, imidazol-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, 1-oxo-thiomorpholin-4-yl or 1,1-dioxo-thiomorpholin-4-yl.
The term xe2x80x9c5 or 6 membered heterocyclic groupxe2x80x9d denotes, for example pyridinyl, pyrimidinyl, oxadiazolyl, triazolyl, tetrazolyl, thiazolyl, thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, piperazinyl or piperidyl.
The term xe2x80x9carylxe2x80x9d denotes 5 or 6 membered carbocyclic aromatic compounds or condensed carbocyclic aromatic compounds such as phenyl and naphthyl.
The compounds of formula II can be manufactured according to e.g. WO 00/50398, i.e. by converting a compound of formula 
into the corresponding chloro or bromo acid halide, and by reacting the obtained halide with a compound of formula 
to a compound of formula II, wherein the definition of the substituents is given above.
Compounds of general formula I can be manufactured, on their turn, by successively alkylating (twice) a compound of formula 
with an R3a-halide (in the presence of a strong base such as BuLi) to a compound of general formula 
and I, respectively.
This method for manufacturing the compounds of general formula I is high-yielding but requires the use of the expensive starting materials of formula IV. Furthermore, the dialkylated product of general formula I may contain rather high quantities of the mono alkylated intermediate V and/or of over alkylated compounds, e.g. at the benzene ring. These by-products are quite difficult to remove by crystallization and their concentration in the final product mixture strongly varies in accordance with the reaction conditions. Consequently the above process is unsuitable for scale-up.
Alternatively, the acid of formula IV can be converted into the corresponding ester of formula 
wherein R2a, R2b, R3a, R3b have the significance given above and R7 is lower alkyl. The ester of formula VI is then dialkylated and subsequently saponified (or hydrolyzed) to the compound of formula I.
The second variant of the state-of-the-art method allows to overcome the above purification problem, but it involves an additional esterification/saponification (hydrolysis) step, thus still increasing the costs and complexity of the whole manufacturing process.
The problem at the root of the present invention is therefore to provide a process for preparing the compounds of formula I which can overcome the disadvantages mentioned above.
This problem is solved, according to the invention, by a process for preparing the compounds of formula I comprising the steps of:
reacting a Grignard derivative of a compound of formula 
xe2x80x83wherein X is Cl, Br or I, with a compound of formula 
xe2x80x83to a compound of formula 
xe2x80x83carbonylating the compound of formula IX in the presence of a strong acid, wherein the compound of formula I is obtained.
The process according to the present invention allows to obtain yields which are higher than those provided by the above described conventional process, no major side-products are observed and no complex purification operations are necessary.
Furthermore, the reactants used (formulae VII and VIII) are much cheaper than those applied in the above conventional processes (compounds of formula IV) and are easily available on the market, so that the overall manufacturing costs of compounds of formula I, and therefore also of compounds of formula II, are strongly decreased.
The process according to the present invention is therefore suitable for the scale-up production of the compounds of formula II.
According to a preferred embodiment of the present invention R2a, R2b are, independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkyl substituted by halogen, lower alkoxy, or cyano, and R3a, R3b are independently selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl or, alternatively, R3a and R3b taken together form xe2x80x94(CH2)nxe2x80x94 with n=2,3 or 5.
According to another preferred embodiment of the present invention, R2a and R2b are independently selected from the group consisting of lower alkoxy; lower alkoxy carbonyl; lower alkyl and lower alkyl substituted by halogen; and R3a and R3b are independently lower alkyl or, alternatively, R3a and R3b taken together form xe2x80x94(CH2)5xe2x80x94.
According to a still more preferred embodiment of the invention, the process is applied for the manufacture of 2-(3,5-bis-trifluoromethyphenyl)-2-methyl-propionic acid.
The Grignard reaction (step a) takes place in an ether, such as diethyl ether, tetrahydrofuran, dipropyl ether, dibutyl ether and the like, or in a mixture of ethers and aromatic solvents such as toluene and xylene. The reaction is carried out at atmospheric pressure and at a temperature varying between about 15xc2x0 C. and the boiling point of the reaction mixture itself (reflux). The purity of the alcohol intermediate of formula IX is not critical; it can be as low as 70%, for preparing the acid of formula I in a purity of at least 97%.
The carbonylation reaction (step b) is preferably performed at a temperature varying between about xe2x88x9220xc2x0 C. and about 60xc2x0 C., more preferably between about 10xc2x0 C. and about 30xc2x0 C., and in the presence of a chlorinated solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and dichlorobenzene.
The addition of a strong acid is necessary for the carbonylation reaction to proceed. Preferred acids are the fluorinated sulfonic acids of formula CnF2n+1SO3H (n=0-20, preferably 0-6), C2F5Oxe2x80x94C2F4SO3H and mixtures thereof. The acids FSO3H, CF3SO3H and mixtures thereof are particularly preferred. The strong acid is preferably added in amounts varying between about 1 and about 10 molar equivalents, preferably between about 2 and about 5 molar equivalents.
According to a preferred embodiment of the present invention water is added to the reactants mixture of step b) in an amount up to about 5 molar equivalents (relative to the alcohol of formula IX), preferably in an amount varying between about 0.1 and about 1 molar equivalents and, still more preferably, in an amount varying between about 0.2 and about 0.7 molar equivalents. The addition of water is not mandatory but it generally enables a reproducible increase of the selectivity towards the compound of formula I. The addition of a reagent such as formic acid, which under the reaction conditions decomposes to give water and CO, has the same effect.
The carbonylation may take place at pressures of CO varying between about 1 and about 500 bar, preferably between about 10 and about 100 bar and, even more preferably, between about 20 and about 60 bar.
The concentration, defined as gram of alcohol of formula IX per gram of solvent used, may vary between about 1 and about 30%, preferably between about 1 and about 15%, without implying major consequences on yield and selectivity towards the compounds of formula I.
In order to avoid possible decomposition of the alcohol IX during the charging of the reactor, i.e. before the carbonylation starts, it may be appropriate, on a large scale, to add it to the mixture of solvent, acid and water (if necessary), already under CO pressure. The carbonylation reaction is then almost instantaneous. Accordingly, the carbonylation step may take place either in a semi-batch or in a continuous flow reactor.
Another aspect of the present invention concerns a process for the manufacture of compounds of formula II comprising the subsequent steps of converting a compound of formula I into the corresponding chloro or bromo acid halide and reacting the halide with a compound of formula III to a compound of formula II, wherein the compound of formula I is obtained by the steps of:
reacting a Grignard derivative of a compound of formula VII with a compound of formula VIII, to a compound of formula IX; and
carbonylating the compound of formula IX wherein the compound of formula I is obtained.
Preferably, the process according to the present invention is applied for preparing therapeutically active compounds 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide or 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-morpholin-4-yl-4-o-tolyloxy-pyrimidin-5-yl)-isobutyramide.